臺灣博碩士論文加值系統

化合物LY181984及LY186641為Eli Lilly藥廠最近篩選出對固態腫瘤具有
廣泛抑制作用,但對血癌細胞反而無效.然而,此類化合物之作用機轉不同
於傳統的抗癌藥物.目前為止,真正的作用機轉仍不清楚,實驗結果推測粒
線體為主要的作用部位.對DNA,RNA及蛋白質之合成沒有抑制作用,所以它
對細胞的副作用低,沒有骨髓抑制及胃腸出血等副作用,引起廣泛的注意.
由於具有酸性的sulfonylurea類化合物,在親核性溶劑中不安定,容易分
解.因此,本研究即以LY181984為引導化合物,將化合物LY181984的 urea部
份以N-hydroxyguanidine取代,經體外毒殺癌細胞活性試驗,結果証實仍保
有良好的抗腫瘤活性,如化合物N-(4-chlorophenyl)-N'-[3,5-
dichloro-4-(4-nitrophenoxy)benzenesulfonyl]-N"-hydroxyguanidine
及化合物N-(4-chlorophenyl)-N'-[3,5-dichloro-4-(2-chloro-4-nitro
phenoxy)benzenesulfonyl]-N"-hydroxyguanidine,顯示N-hydroxy-
guanidine在此可作為urea之bioisoster,而成為有效的抗腫瘤藥物.本實
驗室為合成較大基團之diarylsulfonylurea衍生物,將鄰近磺胺基之苯環
以benzo[b]thiophene, benzo-2,1,3-thiadiazole等雜環或以二個相互連
接的芳香環,如2-(pyrid-2-yl)thiophene, 5-(isoxazol-3- yl)
thiophene和2-(3-[1-methyl(trifluoromethyl)pyrazolyl]) thiophene
取代,仍保有抗腫瘤活性.若以2-[(pyrid-2-yl)sulfonyl] thiophene取代
時,唯獨化合物3特別有效外,抗腫瘤活性大都不佳.當以4-
phenoxybenzene取代時,抗腫瘤活性都大大的提昇.由於N-
hydroxyguanidine成功地取代urea,合成之N-hydroxy- guanidine衍生物,
不但可以增加藥物之安定性,同時具有抗癌活性,所以本論文也企圖合成
sulfonyl N-cyanoguanidine衍生物,來取代sulfonylthio urea,可惜反應
失敗無法達成.

LY181984 and LY186641 are potent anticancer drugs with broad
spectrum of activity against murine solid tumors, but inactive
against both leukemia L1210 and P388. However, the mechanism of
action of LY181984 appears to be different from previously
known classes of oncolytics. At present the mechanism of
cytoyoxicity is not clear. Initial studies on the mechanism of
action indicated that these compounds did not inhibit DNA, RNA
or protein synthesis. Preliminary data implicated that
mitochondria may be the potential site of action. Nevertheless,
low toxicity in myelosuppression and the lack of
gastrointestinal toxicity, rise of this type of compounds give
attention. However, this type of diarylsulfonylurea derivatives
are acidic compounds and are susceptible to hydrolysis in
solution. We proposed and synthesized a series of sulfonyl N-
hydroxy guanidine derivatives as modification of
diarylsulfonylureas. A cytotoxic activity against several solid
tumor cell lines were evaluated with MTT method. The results
indicated that N-(4- chlorophenyl)-N'-[3,5-dichloro-4-(4-
nitrophenoxy)benzenesulfonyl ]-N"-hydroxyguanidine and N-(4-
chlorophenyl)-N'-[3,5-dichloro-4- (2-chloro-4-nitrophenoxy)
benzenesulfonyl]-N"-hydroxyguanidine possessed broad spectrum
and potent activity against solid tumors, indicatind that N-
hydroxyguanidine group can be considered as a bioisoster to
urea in this case. In order to investigate the effect of
hydrophobicity on antitumor effect, a series of
diarylsulfonylurea compounds with a bulky substitution on
sulfonamide portion have been synthesized as well. Some of the
compounds showed potent cytotoxicity against solid tumor cell
lines, with N-(4-chloro- phenyl)-N'-[(2-[3-chloro-5-
trifluoromethylpyrid-2-yl]sulfonyl)- thiophene-5-sulfonyl]urea
is the most potent compound in this series. Some are even
better than LY181984. Futhermore, an attempt to replace the
thiourea moiety of diarylsulfonylthiourea with N-cyanoguanidine
was unsuccessful.